Lysophosphatidic acid (LPA) is a physiologically active phospholipid which is present in a living body. LPA transduces a signal in a cell and modulates the proliferation, differentiation, survival, migration, adhesion, infiltration, morphogenesis of a cell by binding to a specific G-protein-coupled receptor (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6). Further, it has been known that LPA is involved with a disease accompanied with fibrosis in various organs.
Regarding liver, it has been reported that LPA accelerates the proliferation or contraction of stellate cell which plays an important role in the process of hepatic fibrosis, or the migration of myofibroblast (refer to Non-Patent Documents 1, 2 and 3).
Regarding kidney, it has been reported that the production of LPA or the expression of LPA1 is facilitated in a mouse with unilateral ureteral ligation, which is an animal model of renal fibrosis, and that the renal fibrosis is suppressed by LPA1 deficiency or administration of an LPA receptor-antagonist (refer to Non-Patent Documents 4 and 5).
Regarding lung, it has been reported that the LPA concentration in bronchoalveolar lavage fluid of a patient with idiopathic pulmonary fibrosis is elevated; and that LPA1 is most expressed in fibroblast having an important role in the process of pulmonary fibrosis and LPA makes the fibroblast migrate. Further, it has been reported that fibrosis is suppressed by LPA1 deficiency or administration of an LPA receptor-antagonist in a mouse to which bleomycin was intratracheally administered, which is an animal model of pulmonary fibrosis (refer to Non-Patent Documents 6 and 7).
Regarding skin, it has been reported that fibrosis of skin is suppressed by LPA1 deficiency or administration of an LPA receptor-antagonist in a mouse to which bleomycin was subcutaneously administered, which is a sclerodermia animal model (refer to Non-Patent Document 8).
It has also been known to that LPA is involved with immunological or inflammatory diseases. It has been reported that LPA facilitates the migration of human monocyte; and that LPA is involved with the proliferation or infiltration of T cells. Further, it has been reported that synovial cells of patient with rheumatoid arthritis express LPA receptor and migrate or produce IL-6 and IL-8 by the LPA stimulation; and that these actions are inhibited by an LPA receptor antagonist (refer to Non-Patent Documents 9, 10 and 11).
In addition, it has been reported that LPA and LPA1 are involved with the development of neuropathic pain (refer to Patent Document 12); that LPA is involved with urologic diseases by contracting an extracted urethra specimen and a prostatic specimen to increase the intraurethral pressure (refer to Patent Document 1); and that LPA is involved with cancer-related diseases by accelerating the infiltration of cancer cells, by accelerating the proliferation of ovary cancer cells, or by accelerating the proliferation of prostate cancer cells (refer to Non-Patent Documents 13, 14 and 15).
Based on these findings, a medicament which antagonizes the LPA receptor (particularly, LPA1 receptor) is considered to be useful for the prevention and/or treatment of a disease accompanying fibrosis, an immunological or inflammatory disease, a central or peripheral nervous system disease, an urologic disease, a cancer-related disease, etc.
On the other hand, as a compound having antagonizing action of LPA receptor, ([1,1′-biphenyl]-4-yl)acetic acid derivatives are disclosed in Patent Documents 2 to 19, and Non-Patent Documents 7, 8, 16 and 17; (2′-methoxy-[1,1′-biphenyl]-4-yl) acetic acid derivatives are disclosed in Patent Document 17; and 3-chloroisothiazole derivatives are disclosed in Patent Document 19, but there is no disclosure on the compound of the present invention.